EXTRACTABLES & LEACHABLES - A Practical Approach to Extractables & Leachables

INTRODUCTION

The study of extractables and leachables (E&L) has been evolving for many years. As pharmaceutical manufacturers, packaging vendors, and regulatory agencies gain more knowledge of extractable compounds, the scope of E&L guidelines grows with it. Many of the case studies that initiated interest in extractables and leachables are based on primary packaging. In some cases, the secondary or tertiary packaging were identified as sources of leachables. As a result, the primary emphasis of extractables screens has been on the packaging systems. The approach to these screens is well established. The first iterations of regulatory guidance addressed the common packaging materials in the United States Pharmacopeia (USP) chapter <661>, which relied heavily on physiochemical testing to characterize the material of construction but did not directly address extractables testing of the final packaging materials in detail. With advancements in the manufacture of plastics and increasing variety of base polymers used for packaging systems, it became evident that more specific guidelines are needed.

In an effort to provide clarity with respect to extractables and leachables used in primary packaging and the manufacture of drug products, USP introduced a series of chapters specifying the approach to characterize and qualify both packaging and manufacturing systems with respect to patient safety. USP chapter <661> was split in two: chapter <661.1> Plastic Materials of Construction, which deals with identification, physiochemical properties, and bioreactivity of the materials of construction only, and <661.2> Plastic Packaging Systems for Pharmaceutical Use, which addresses the final packaging system and establishes its suitability for intended use. Additionally, as the components used in manufacturing become of increasing interest as sources of potential leachables, the industry must prepare for the new guidelines. Furthermore, the rising popularity of biologics and the relative complexity of their manufacture warrants a comprehensive framework for determining the risk of drug-product-material interaction. A systematic approach to addressing these materials more specifically is introduced in draft USP chapters <665> Polymeric Components and Systems Used in the Manufacture of Pharmaceutical and Biopharmaceutical Drug Product and <1665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products. While the latter two chapters are not yet official, the purpose of these chapters is to explicitly include requirements for extractables and leachables, it is prudent to get acquainted with the content.

The final chapter, which became effective in conjunction with <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems is <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems. The purpose of this chapter is to outline the basis of a leachables assessment of packaged drug product, the determination of an appropriate analytical evaluation threshold, and to establish an extractables-leachables correlation. Guidelines for the long-term strategy for monitoring target compounds, such as method validation, development of specification, etc. are also listed in this chapter.

Despite developing regulation, it is not possible to list the best approach for each drug product packaging or manufacturing configuration in these chapters, as each of these chapters refers the reader to the extractables foundation chapter <1663> for the for the design, justification, and execution of an extractables assessment.¹

THE EXTRACTABLES SCREEN

USP chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems is the basis for the chemical safety assessment section of USP <661.2>, the organic extractables profile of draft USP <665>, and the chemical safety qualification of draft USP <1665>. It is, therefore, the cornerstone to determine whether a packaging system is suitable for its intended use and free from process equipment-related leachables at levels of toxicological concern. A primary packaging extractables screen classically includes exposing the primary packaging to conditions far greater than it will ever encounter, in order to build a worst-case profile. The key characteristics of a scientifically rigorous extractables study generally include driving analytes into solution in the laboratory for subsequent analysis via a variety of complementary techniques. The critical parameters for any extraction study are:

– A range of solvents for purposes of targeting a variety of potential leachables

– Conditions appropriate for the drug product/packaging system configuration

– Generation of extracts that contain potential leachables at levels that exceed the sensitivity of the analytical methods

– Complementary analytical methods that combine to develop a worst-case leachables profile

Extract generation should occur in a medium that mimics the formulation and brackets the pH range of the final product to target organic extractables. A third solvent to target organic extractables is an aggressive solvent designed to generate the maximum concentration of potential leachables without compromising the integrity of the container. In addition, a solvent designed to drive any inorganic leachables into solution should be used. By employing a range of solvents, the solutions are more likely to include leachable compounds with diverse properties; however, the extraction conditions are also important.

Solvent selection establishes the appropriate media into which the extractables will be observed, but time and temperature are what will drive the extraction. Since the goal of the study is to simulate the duration of shelf-life in a condensed period of time, the use of Arrhenius scaling is recommended to determine the appropriate level of aging in the laboratory.¹ Exposing the packaging system to extreme conditions is best applied to componentry that will be in direct contact with the formulation for the duration of the drug product shelf-life. However, due to short exposure time and relatively mild conditions that a component used for manufacturing is in contact with the formulation an extractables screen of these materials can employ much milder conditions and fewer solvents.

SIMULATING EXTRACTABLES IN MANUFACTURING SURFACES

Many components used in the manufacture of drug products are polymeric single-use systems (SUS). Single-use systems are gaining popularity for a variety of reasons: mitigating costly cleaning validations, minimizing “down-time” in between batches, and as is often the case for biopharmaceutical manufacturing, may be the only substrate suitable for manufacture. Consequently, the expansive options of SUS on the market must also be deemed suitable for their intended use, but the means to that determination does not require the extreme conditions typically used for packaging systems. Traditional extraction techniques may be used, but they carry the risk of degrading the test article, which results in lengthy justification for extractable compounds that will not be observed as leachables. The transient exposure of a drug product formulation to the manufacturing component justifies a “softer” approach to the extractables screen. By simulating slightly exaggerated manufacturing conditions in the lab, the study can account for potential extractables in line with the probability that they will be observed in real-time and mitigate the aforementioned risks.

Simulation studies can be limited to two solvents and exposure conditions chosen to extend slightly beyond manufacturing conditions, as a complete profile can be obtained with this simplified approach. For example, using placebo or drug product as an extraction solvent will serve as a representative of the manufacturing process. An aggressive solvent can be used as a second extraction solvent to aid qualitative evaluation of the formulation sample and represent a positive control. Using an aggressive solvent has the additional benefit of showing the analytical methods are capable of detecting the target compounds.

CHARACTERIZING THE EXTRACTS

It is important to perform the extraction at a scale that will yield concentrations of leachables at levels that will be analytically significant in order to characterize the extracts. This may be accomplished at the time of preparation or via manipulation of the test solution after extraction.

Extract characterization is best performed using complementary analytical techniques. Mass spectrometry coupled with chromatographic systems (such as gas or liquid) are powerful investigative tools that will provide structural information needed to categorize and/or identify organic extractable compounds. Gas chromatography-mass spectrometry (GC/MS) analytical methods must be designed to detect organic compounds across a range of boiling points to capture semi-volatile and volatile extractables. Liquid chromatography-mass spectrometry (LC/MS) methods, though limited in peak identification capabilities, can provide valuable structural information of non-volatile extractables. In many cases, the identity of a compound can be ascertained through the use of commercially available libraries, internal databases, and in-house expertise. In the case where a compound cannot be readily identified, structural analysis may be performed in order to glean any potentially useful information. Analysis for inorganic compounds, commonly referred to as “extractable metals,” can be evaluated using Inductively-Coupled Plasma Mass Spectrometry (ICP/MS). ICP/MS is the most common platform for assessing elemental impurities, and the same techniques can be used to determine elemental leachables.

DETERMINATION OF THE ANALYTICAL EVALUATION THRESHOLD

Pairing the appropriate extraction conditions with a conservative Analytical Evaluation Threshold (AET) results in a well-rounded profile of potential leachables in packaging systems or manufacturing equipment. The AET for extraction studies is one of the most critical elements of the study design because it represents the threshold for which the applicant commits to further investigation if a compound is observed. It is the threshold for which the packaging system or manufacturing equipment may be deemed safe for its intended use. Therefore, it is imperative to design the study such that the resulting solutions contain concentrations of compounds of interest, if present, above this threshold in order for the data to support this conclusion.

The AET is the link between a Safety Concern Threshold (SCT) published by various agencies that determine acceptable daily intake of potentially toxic compounds and the specific drug product. The SCT for genotoxic compounds which is 1.5 μg/day per USP, Product Quality Research Institute (PQRI), and International Conference on Harmonisation (ICH) guidelines is the most common basis for the AET as it is the most conservative for oral and parenteral drug products.^2-9 To calculate the AET the maximum daily dose of the drug product and the SCT are combined with a 50% uncertainty factor to accommodate variations in response of the target compounds. The final AET is a drug product specific value typically expressed in units per component or units per day. For example, AET calculation (μg/vial) for primary packaging, daily dose one vial per day:

When scaling this calculation for manufacturing surfaces, the AET will often be milligram-level per batch because the batch size is typically tens or hundreds of liters, or thousands of vials. Consider the aforementioned example, applied to a manufacturing scale batch size, AET calculation (μg/component) for manufacturing surfaces, 20L batch size for a 1.5 mL fill:

Due to the size and complexity of many components of typical manufacturing processes, none of which is anticipated to exceed one kilogram in total weight, a more conservative approach is a materials-based AET of 1 μg/g of material. If a component does weigh one kilogram, this AET represents a ten-fold more conservative AET, as shown in the following calculation:
The extraction screen is intended to represent a worst-case scenario of potential leachables. The studies are designed to mimic shelf-life under extreme conditions. The leachables assessment is the final step in the evaluation process. The core concepts of analysis and AET previously discussed are applied to aged drug product. Drug product, aged under accelerated conditions, is analyzed for the same range of compounds. In this context, however, if these compounds are observed, they can be considered bona fide leachables rather than potential leachables. Moving forward, the applicant will have to consider next steps by referring to a toxicologist for recommendations on specific compounds, validating methods for monitoring target compounds on stability, or in the event no leachables are observed, justifying completion of the leachables assessment.

The completeness of an extractables and leachables assessment hinges on the goals of the study. If scientifically sound principles are used to justify the study design, parameters appropriate for the drug product surface interaction, and a sufficiently conservative AET are selected, then an applicant can confidently conclude whether their packaging system is suitable for its intended use and free from process equipment-related leachables. A leachables assessment of aged drug product will support the justification of compliance or direct the continued monitoring over time, if compounds are observed.

The implications of upcoming regulatory guidelines have the potential to compromise the timelines of pharmaceutical and biopharmaceutical applicants as vendors implement internal strategies to align with evolving regulation. After significant industry feedback, applicants were permitted to defer to the original <661>, but the implementation window for chapters <661.1> and <661.2> closes in early 2020. The draft chapters <665> and <1665> are in the pipeline. Therefore, it is imperative to understand the underlying principles of foundation chapter <1663> and apply the concepts therein to prepare a complete assessment of potential leachables in drug product manufacturing or packaging systems.

REFERENCES

1. USP Chapter 661, Plastic Packaging and Their Materials of Construction, USP 41.
2. SP Chapter 661.1, Plastic Materials of Construction, USP 41.
3. USP Chapter 661.2, Plastic Packaging Systems for Pharmaceutical Use, USP 41.
4. SP Chapter 1663, Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, USP 41.
5. USP Chapter 1664, Assessment of Leachables Associated with Pharmaceutical Packaging/Delivery Systems, USP 41.
6. ICH M7, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.
7. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiative for Parenteral and Ophthalmic Drug Product (PODP, PDA, J PharmaSci and Tech, 2013, 67 430-447.
8. Draft USP Chapter 665, Polymeric Components and Systems Used in the Manufacture of Pharmaceutical and Biopharmaceutical Drug Product, USP Pharmacopeial Forum (PF) 43(3) [May–Jun. 2017].
9. Draft USP Chapter 1665 Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products, USP Pharmacopeial Forum (PF) 43(3) [May–Jun. 2017].

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Cheryl Johnson is the Commercial Development Manager of Biotechnology at Alcami. She has more than 15 years of industry experience in research and manufacturing scale laboratories, and her areas of expertise include analytical and preparative chromatography, mass spectrometry, method development, and validation with specialized knowledge of regulatory compliance relating to extractables and leachables. She joined Alcami in 2014 as a scientist and is a technical lead for Alcami’s Biotechnology and Structural Chemistry-related offerings.